3-{(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl}-3-oxo-propanenitrile, 2-hydroxypropane-1,2,3-tricarboxylate described as FORMULA I below and as disclosed in WO 02/096909, U.S. Pat. No. 7,301,023. US FDA approved it for rheumatoid arthritis.

The key step for the preparation of 3-{(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl}-3-oxo-propanenitrile as depicted in (Scheme-1) WO 02/096909 includes:                (i) resolution of racemic (1-Benzyl-4-methylpiperidin-3-yl)-methylamine to (3R,4R)-(1-Benzyl-4-methylpiperidin-3-yl)-methylamine using Di-p-toluoyl-L-tartarate;        (ii) condensation of 4-Chlropyrrolo[2,3-d]pyrimidine with (3R,4R)-(1-Benzyl-4-methylpiperidin-3-yl)-methylamine to get (3R,4R)-(1-benzyl-4-methylpiperidin-3-yl)methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine; and        (iii) debenzylation of (3R,4R)-(1-Benzyl-4-methylpiperidin-3-yl)methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine followed by condensation with cyano acetic acid derivative to get 3-{(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl}-3-oxo-propanenitrile (FORMULA I), (Scheme-1).        

The most important part for the preparation of FORMULA I is the synthesis of (3R,4R)-(1-Benzyl-4-methylpiperidin-3-yl)-methylamine as it is very tedious synthesis and also requires very expensive reagent. There are several processes reported in literature for the synthesis and resolution of racemic (1-Benzyl-4-methylpiperidin-3yl)-methylamine to (3R,4R)-(1-Benzyl-4-methylpiperidin-3-yl)-methylamine.
WO 2007/012953 discloses preparation of 1-Benzyl-3-methoxycarbonylamino-4-methyl-pyridinium bromide and it's asymmetric reduction using mixture of Ruthenium and Iridium based chiral catalysts under hydrogenation condition to provide (3R,4R)-(1-Benzyl-4-methylpiperidin-3-yl)-methylamine with 84% cis isomer, having 68% ee.
The patent further discloses the preparation of same intermediate by applying partial reduction followed by asymmetric reduction approach to obtain highly enriched Piperidine derivative as depicted in Scheme-2.

Both the approaches make use of very high chiral catalyst loading and render their commercial use expensive and difficult. Further, the process requires very high pressure which makes it risky, costlier and unfavorable for scale up.
WO 2010/123919 provides an additional process for preparation of (1-Benzyl-4-methylpiperidin-3-yl)-methylamine, which includes:                (i) protection of amino group of 3-Amino-4-methyl pyridine with Dimethyl carbonate in presence of Potassium tert-butoxide in Tetrahydrofuran;        (ii) quaternization of Nitrogen of Pyridine system using Benzyl bromide in Toluene;        (iii) partial reduction of the quaternized Pyridine system to produce 1,2,5,6-Tetrahydropyridine in presence of Sodium borohydride in Methanol;        (iv) reduction with Platinum oxide in Methanol provides Piperidine derivative. Followed by the purification by column chromatography; and        (v) further reaction with Lithium aluminium hydride and purification by column chromatography to get (1-Benzyl-4-methyl-piperidin-3-yl)-methylamine.        
The process has several drawbacks. Overall process yield is very poor i.e. approximately 40%. The process uses column chromatography at two stages. Lithium aluminum hydride, a known pyrophoric reagent, account for the safety risk during its manufacturing. Lastly Platinum oxide is very explosive in presence of hydrogen. It is very costly reagent which discourages its use on plant scale. Overall the process is costlier, not so safe to work on commercial scale and demands stringent skill of art.
WO 2010/123919 further reveals an additional procedure for the preparation of (1-Benzyl-4-methylpiperidin-3-yl)-methylamine and the synthetic procedure is summarized in Scheme-3.

Process involves debenzylation and quaternization of ethyl 1-Benzyl-3-oxopiperidine-4-carboxylate followed by protection of the resulted Ethyl 3-oxopiperidine-4-carboxylate derivative using di-tert-butyl dicarbonate. Protected Piperidine derivative was methylated by abstracting the Methylenic proton using Sodium hydride and further reaction with Iodomethane. In the next stage deprotection of N-tert-butoxycarbonyl group was carried out in acidic media, and the resulting 4-Methylpiperidin-3-one was benzylated followed by reductive amination with Methylamine and Sodium triacetoxyborohydride provide the desired product (1-Benzyl-4-methylpiperidin-3-yl)-methylamine.
The overall conversion involves five stages from quite a complex starting material. The process involves protection and deprotection in different stages. Use of costly, non safe reagents such as Sodium hydride and lacrimatic Benzyl bromide and Sodium triacetoxyborohydride limit its commercial scale production. The process has major draw back with respect to the use of column chromatography at three stages. Moreover disclosure of process is silent about the purity of intermediates and of the target molecule produced. The overall yield mentioned for the process is also very low i.e. 13.6 molar percent.
U.S. Pat. No. 6,627,754 provides a similar reductive amination route as discussed in WO 2010/123919 for the synthesis of (1-Benzyl-4-methyl piperidin-3-yl)-methylamine from 1-Benzyl-4-methylpiperidin-3-one in a sealed tube using Sodium triacetoxyborohydride as a reducing agent. Sodium triacetoxyborohydride is extremely moisture sensitive pyrophoric reagent. Sealed tube reaction is difficult to execute on large scale.
The processes taught by prior art have several drawbacks namely expensive, not suitable for scale up at plant level, energy intensive, difficult, giving lower yields, forcing use of corrosive acids, longer duration of corrosive reactions and less user friendly. Considering the drawbacks of prior art and very complex methodologies applied, for the preparation of the (1-Benzyl-4-methyl piperidin-3-yl)-methylamine, there is a urgent and pressing need for simple, energy economical, financially cheaper plant friendly process, environment friendly process for the preparation of (3R,4R)-(1-Benzyl-4-methylpiperidin-3-yl)-methylamine to synthesize FORMULA I that does not use hygroscopic and pyrophoric chemicals and yet provides better yields.